Variation in the PTH2R gene is associated with age-related degenerative changes in the lumbar spine

Åkesson, Kristina; Tenne, Max; Gerdhem, Paul; Luthman, Holger; McGuigan, Fiona

doi:10.1007/s00774-013-0550-x

Cited by 9 publications

(9 citation statements)

References 29 publications

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“…Also, TRPS1 contributes to osteoblast differentiation (Piscopo et al 2009). The parathyroid hormone-2 receptor (PTH2R) plays a role in the control of proliferation and differentiation of growth plate chondrocytes (Akesson et al 2015;Panda et al 2009). Variation in the PTH2R is associated with age-related vertebral degenerative changes (Akesson et al 2015) and may contribute to early-onset generalized OA (Meulenbelt et al 2006).…”

Section: Discussionmentioning

confidence: 99%

Polygenic risk score for disability and insights into disability-related molecular mechanisms

et al. 2019

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Late life disability is a highly devastating condition affecting 20% or more of persons aged 65 years and older in the USA; it is an important determinant of acute medical and long-term care costs which represent a growing burden on national economies. Disability is a multifactorial trait that contributes substantially to decline of health/wellbeing. Accordingly, gaining insights into the genetics of disability could help in identifying molecular mechanisms of this devastating condition and age-related processes contributing to a large fraction of specific geriatric conditions, concordantly with geroscience. We performed a genome-wide association study of disability in a sample of 24,068 subjects from five studies with 12,550 disabled individuals. We identified 30 promising disability-associated polymorphisms in 19 loci at p < 10 −4 ; four of them attained suggestive significance, p < 10 −5. In contrast, polygenic risk scores aggregating effects of minor alleles of independent SNPs that were adversely or beneficially associated with disability showed highly significant associations in meta-analysis, p = 3.13 × 10 −45 and p = 5.60 × 10 −23 , respectively, and were replicated in each study. The analysis of genetic pathways, related diseases, and biological functions supported the connections of genes for the identified SNPs with disabling and age-related conditions primarily through oxidative/ nitrosative stress, inflammatory response, and ciliary signaling. We identified musculoskeletal system development, maintenance, and regeneration as important components of gene functions. The beneficial and adverse gene sets may be differently implicated in the development of musculoskeletal-related disability with the beneficial set characterized, e.g., by regulation of chondrocyte proliferation and bone formation, and the adverse set by inflammation and bone loss.

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Section: Discussionmentioning

confidence: 99%

Polygenic risk score for disability and insights into disability-related molecular mechanisms

et al. 2019

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“…Over the past decades, extensive genetic and genomic studies have conducted to discover genes/SNPs associated with BMD variation in human populations . However, our understanding about the underlying association mechanism is very limited.…”

Section: Discussionmentioning

confidence: 99%

“…Over the past decades, extensive genetic and genomic studies have conducted to discover genes/SNPs associated with BMD variation in human populations. [29][30][31][32][33][34] However, our understanding about the underlying association mechanism is very limited. Besides, a majority of phosSNPs in the GPS 2.0 database were predicted, and their potential effects on protein phosphorylation have not been validated by experiments.…”

Section: Discussionmentioning

confidence: 99%

Why SNP rs227584 is associated with human BMD and fracture risk? A molecular and cellular study in bone cells

Zhou

Qiu

et al. 2018

J Cellular Molecular Medi

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A large number of SNPs significant for osteoporosis (OP) had been identified by genome‐wide association studies. However, the underlying association mechanisms were largely unknown. From the perspective of protein phosphorylation, gene expression regulation, and bone cell activity, this study aims to illustrate association mechanisms for representative SNPs of interest.We utilized public databases and bioinformatics tool to identify OP‐associated SNPs which potentially influence protein phosphorylation (phosSNPs). Associations with hip/spine BMD, as well as fracture risk, in human populations for one significant phosSNP, that is, rs227584 (major/minor allele: C/A, EAS population) located in C17orf53 gene, were suggested in prior meta‐analyses. Specifically, carriers of allele C had significant higher BMD and lower risk of low‐trauma fractures than carriers of A. We pursued to test the molecular and cellular functions of rs227584 in bone through osteoblastic cell culture and multiple assays.We identified five phosSNPs significant for OP (P < 0.01). The osteoblastic cells, which was transfected with wild‐type C17orf53 (allele C at rs227584, P126), demonstrated specific interaction with NEK2 kinase, increased expression levels of osteoblastic genes significantly (OPN, OCN, COL1A1, P < 0.05), and promoted osteoblast growth and ALP activity, in contrast to those transfected with mutant C17orf53 (allele A at rs227584, T126).In the light of the consistent evidences between the present functional study in human bone cells and the prior association studies in human populations, we conclude that the SNP rs227584, via altering protein‐kinase interaction, regulates osteoblastic gene expression, influences osteoblast growth and activity, hence to affect BMD and fracture risk in humans.

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“…Parathyroid hormone (PTH) is a key regulator of calcium metabolism and contributes to skeletal development by regulating chondrocyte proliferation and differentiation during early bone growth 34 . Previous genetic studies have linked other PTH genes with age-related degenerative changes in lumbar spine 35 and BMD 20 . In this study, we identified a three-SNP haplotype (rs12425376-rs10843047-rs42294, P = 5.75 × 10 −6 ) that was significantly associated with the diagnosis of OP.…”

Section: Discussionmentioning

confidence: 99%

Endochondral ossification pathway genes and postmenopausal osteoporosis: Association and specific allele related serum bone sialoprotein levels in Han Chinese

Zhang

Liu²,

Zhang

et al. 2015

Sci Rep

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Osteoporosis is a systemic skeletal disorder characterized by reduced bone mineral density (BMD) and disrupted bone architecture, predisposing the patient to increased fracture risk. Evidence from early genetic epidemiological studies has indicated a major role for genetics in the development of osteoporosis and the variation in BMD. In this study, we focused on two key genes in the endochondral ossification pathway, IBSP and PTHLH. Over 9,000 postmenopausal Han Chinese women were recruited, and 54 SNPs were genotyped. Two significant SNPs within IBSP, rs1054627 and rs17013181, were associated with BMD and postmenopausal osteoporosis by the two-stage strategy, and rs17013181 was also significantly associated with serum IBSP levels. Moreover, one haplotype (rs12425376-rs10843047-rs42294) covering the 5’ end of PTHLH was associated with postmenopausal osteoporosis. Our results provide evidence for the association of these two key endochondral ossification pathway genes with BMD and osteoporosis in postmenopausal Han Chinese women. Combined with previous findings, we provide evidence that a particular SNP in IBSP has an allele-specific effect on mRNA levels, which would, in turn, reflect serum IBSP levels.

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Variation in the PTH2R gene is associated with age-related degenerative changes in the lumbar spine

Cited by 9 publications

References 29 publications

Polygenic risk score for disability and insights into disability-related molecular mechanisms

Polygenic risk score for disability and insights into disability-related molecular mechanisms

Why SNP rs227584 is associated with human BMD and fracture risk? A molecular and cellular study in bone cells

Endochondral ossification pathway genes and postmenopausal osteoporosis: Association and specific allele related serum bone sialoprotein levels in Han Chinese

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